Tardive Dyskinesia (TD)

The introduction of chlorpromazine (Thorazine) in 1952 was a major milestone in the treatment of psychotic patients. Other antipsychotic drugs were subsequently added into clinical practice and their use facilitated effective outpatient psychiatric care. However, it soon became apparent that these major tranquilizers, known as neuroleptics, were not without risks. The first chlorpromazine-induced movement disorder was recognized in 1956. Oro-facial-lingual (OFL) stereotypic movement, related to perphenazine, was reported in 1957 and an acute dystonic reaction associated with the use of prochlorperazine was described a year later. The full appreciation of drug-induced movement disorders was delayed partly because involuntary movements were initially attributed to anxiety, agitation, and mannerisms that may occur sporadically in persons with psychiatric disorders even without exposure to antipsychotic medications. Drug-induced movement disorders have gradually emerged as a major problem in clinical psychiatry and medicine. A variety of movement disorders have been characterized and linked to different dopamine receptor blocking drugs (DRBD), also referred to as neuroleptics (see Appendix at the bottom of this page). These drugs are primarily categorized as antipsychotic agents, but DRBD are also used to treat a variety of gastrointestinal disorders such as nausea and gastroparesis. The clinical spectrum of these neuroleptic induced movement disorders (NIMD) ranges from only slight embarrassment or discomfort to life-threatening respiratory dyskinesias, neuroleptic malignant syndrome, and other disorders potentially catastrophic for the patients. Although the new "atypical" neuroleptics promise to have a lower risk for NIMD, this group of iatrogenic movement disorders is still among the most distressing of all neurologic conditions.

Classification of Drug-Induced Movement Disorders

There are many drugs, such as levodopa and dopamine agonists, and some central nervous system stimulants, anticonvulsants, antidepressants, H2 receptor antagonists, hormones, antiarrhythmics, and calcium channel blockers such as cinnarizine and flunarizine, that can affect motor behavior and cause movement disorders. This review will focus only on those movement disorders resulting from exposure to DRBD (neuroleptics). Two major categories of NIMD have been recognized:

Acute (present during the early phase of neuroleptic exposure, usually transient)

Chronic (persistent movement disorder usually occurring during or after a protracted course of neuroleptic therapy, hence the term "tardive" meaning "late-onset")

Subtypes of Neuroleptic Induced Movement Disorders (NIMD)

Subtypes of NIMD are differentiated within these categories according to clinical phenomenology. Such differentiation is important not only because the various disorders probably result from different mechanisms, but also they may require different therapies.

The term "tardive dyskinesia" has been used in the medical literature to refer to any abnormal involuntary movement, usually stereotypic, resulting from exposure to at least one DRBD (for at least three months) and persisting (for at least one month) even after the offending drug has been discontinued. The frequency of TD has been reported to vary between 0.5 and 56 percent in patients receiving antipsychotic medications, with an average estimate at approximately 25 percent. This marked variability is due to differences in diagnostic criteria for TD, patient populations, types of medication, and methods of ascertainment. The risk of TD increases with age and with the dose of DRBD and is particularly high in non-whites and elderly women. In contrast, persistent tardive syndromes are uncommon in children.

The most common type of involuntary movement associated with TD is classified as stereotypy and can be defined as "an involuntary, coordinated, patterned, repetitive, rhythmic, ritualistic, purposeless (but seemingly purposeful) movement, posture or utterance." Simple stereotypies involve only one body part, such as the mouth or hand, whereas complex stereotypies affect more than one body region and may involve the whole body. The OFL movement, most typically seen in TD, is one of the best examples of stereotypies and is present in over 80 percent of patients with TD. In a videotape review of 100 patients with TD evaluated at the Baylor College of Medicine Movement Disorders Clinic, 78 exhibited some stereotypies and 61 of these involved the OFL region. The following OFL stereotypies were observed: chewing, blowing, licking, lip smacking and pursing, facial grimacing, tongue protruding ("fly-catcher's tongue"), and coordinated tongue and mouth movements ("bon-bon sign"). Other stereotypies included hand and toe waving, touching and picking, rubbing of face, scalp and other body parts, head nodding, body rocking, shallow and rapid breathing ("respiratory dyskinesia"), pelvic thrusting ("copulatory dyskinesia"), crossing and uncrossing of legs, shifting of body weight from one to the other leg, pacing or marching in place, alternating sitting and standing, and a variety of vocalizations and noises, such as humming, moaning, and eructations. While TD can result in severe disability, such as shortness of breath due to respiratory dyskinesia, up to two thirds of patients are not even aware of the abnormal involuntary movements. Similar to other hyperkinetic movement disorders, tardive stereotypies are usually exacerbated during stress, disappear during sleep, and may be volitionally suppressed, at least temporarily.

Other involuntary movements associated with TD include chorea (jerk-like movement than move randomly from one body part to another), dystonia (facial spasms, eyelid contractions, clenching of jaws and grinding of teeth, arching of the neck and back, extension of arms), akathisia (feeling of restlessness, inability to stand or sit still, and a need to move), tics (jerk-like coordinated movements often preceded by premonitory sensations), myoclonus (jerk-like simple movements), and a variety of other movements and abnormal, often uncomfortable, sensations.

Treatments

Prevention, rather than treatment, is the ultimate goal of any therapeutic program and this is particularly relevant to TD and other NIMD. Whenever possible, the DRBD should be avoided and used only if other drugs are not available or have failed to control the condition. Once the patient develops symptoms of TD, the responsible neuroleptic should be discontinued if at all possible. The risks of continued exposure the DRBD must be carefully weighed against the possibility of exacerbating the underlying psychiatric or gastrointestinal condition. Discontinuation of DRBD may also cause transient exacerbation of the TD. Nevertheless, stopping the offending drug is usually considered prudent clinical practice. In some patients with psychiatric illness, withdrawal of the antipsychotic agents may not be possible. To minimize TD in such patients, switching to newer, also called atypical neuroleptics might be the only solution. Clozapine and quetiapine are considered the neuroleptics with the lowest risk of developing drug-induced movement disorder. When treatment is required, dopamine-depleting drugs, such as tetrabenazine, provide the most effective treatment of the TD-related involuntary movements. However, these drugs may not completely suppress the involuntary movements and may produce a variety of adverse effects such as daytime drowsiness, insomnia, depression, parkinsonism, and akathisia. The second-line agents including amantadine, benzodiazepines, beta-blockers and levetiracetam, are generally better tolerated but less effective in treating TD. Propranolol, clonidine, gabapentin, opioids have been found useful in some cases of akathisia. Anticholinergic drugs, such as trihexyphenidyl and benztropine, may ameliorate symptoms of tardive dystonia and parkinsonism, but they should not be prescribed routinely because they may possibly precipitate or exacerbate TD. Cholinergic drugs have been extensively tested in the treatment of TD, but they have not been found effective in most recent trials. Injections of botulinum toxin are very effective in the treatment of focal dystonia, such as tardive jaw and face (oromandibular) dystonia. Some cases of disabling TD, resistant to the treatment options listed above, can be potentially treated with a deep brain stimulation surgery.

Appendix

Drugs Causing Movement Disorders: Persons with Parkinson's disease or tardive dyskinesia should be aware that certain drugs can cause parkinsonism and will aggravate already existing symptoms. The following is a partial list of medications that act as blocking dopamine in the brain and are usually prescribed as a potent tranquilizers or antiemetics (drugs used for nausea and vomiting). The drugs listed below are some of the drugs that should be avoided in patients with Parkinson's disease and tardive dyskinesia. However, there may be special reasons to prescribe these drugs in certain circumstances and the patient should discuss that reason with their physicians.